Runchen Miao

Down-regulation of miR-146b-5p by long noncoding RNA MALAT1 in hepatocellular carcinoma promotes cancer growth and metastasis

MicroRNAs play an important role in liver cancer genesis and progression. In this study, we identified down-regulation of miR-146b-5p associated with tumor growth, metastasis and poor survival in hepatocellular carcinoma (HCC) patients. miR-146b-5p could suppress proliferation, migration, and invasion and induced apoptosis in vitro and in vivo. Remarkably, TNF receptor associated factor 6 (TRAF6) was confirmed as a direct target of miR-146b-5p in HCC and miR-146b-5p exerted the tumor suppression roles through inhibiting the phosphorylation of Akt mediated by TRAF6. Furthermore, we identified long non-coding RNA MALAT1 as a molecular sponge of miR-146b-5p to down-regulate its expression in HCC. In general, our results indicate that miR-146b-5p inhibits tumor growth and metastasis of HCC by targeting TRAF6 mediated Akt phosphorylation.

Protective effects of luteolin against acetaminophen-induced acute liver failure in mouse

Acetaminophen (APAP) is widely used as a safety analgesic and antipyretic agent. Although considered safe at therapeutic doses, overdose of APAP can cause acute liver injury that is sometimes fatal, requiring efficient pharmacological intervention. Luteolin is a naturally occurring flavonoid which is abundant in plants. The objective of this study was to investigate corresponding anti-oxidative and anti-inflammatory activities of luteolin, using acetaminophen-treated mice as a model system. Male C57BL/C mice were randomly divided into three groups (n=6 each). The control group was given phosphate buffered saline (PBS) orally. The APAP group was given APAP by intraperitoneal injection (i.p) at 300 mg/kg suspended in PBS. The luteolin-treated group was given APAP and luteolin (0-100 mg/kg/day, 1 or 3 days before APAP administration) suspended in PBS orally. 16 h after APAP administration, the liver and serum were collected to determine the liver injury. Luteolin administration significantly decreased acetaminophen-induced serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), malondialdehyde (MDA) levels, as well as glutathione (GSH) depletion and decrease of superoxide dismutase (SOD). Luteolin restored SOD, GSH and GSH-px activities and depressed the expression of pro-inflammatory factors, such as inducible nitric oxide synthase (i-NOS), TNF-α, nuclear factor kappa B (NF-κB), and IL-6, respectively. Moreover, luteolin down-regulated acetaminophen-induced nitrotyrosine (NT) formation and endoplasmic reticulum (ER) stress. These results suggest the presence of anti-oxidative, anti-inflammatory and anti-ER stress properties of luteolin in response to acetaminophen-induced liver injury in mice.

Model based on γ-glutamyltransferase and alkaline phosphatase for hepatocellular carcinoma prognosis

AIM To determine the prognostic value of alkaline phosphatase (ALP) and γ-glutamyltransferase (GGT) for hepatocellular carcinoma (HCC) . METHODS We analyzed the outcome of 172 HCC patients who underwent liver resection. Receiver operating characteristic (ROC) curve analysis was performed to determine the cut-off value of ALP and GGT. Then, preoperative risk factors for survival were evaluated by multivariate analysis. Based on the significant factors, a prognostic score model was established. RESULTS By ROC curve analysis, ALP > 120 U/L and GGT > 115 U/L were considered elevated. Overall survival (OS) and tumor-free survival (TFS) for patients with elevated ALP and GGT were significantly worse than for patients with ALP and GGT within the normal range. Multivariate analysis showed that the elevated levels of ALP, GGT and tumor size were independent prognostic factors. Giving each positive factor as a score of 1, we established a preoperative prognostic score model. The 5-year OS for patients with a score of 0, 1, 2 and 3 were 84.0%, 45.9%, 44.1% and 0%, respectively, while the TFS was 80.6%, 40.0%, 38.8% and 0%, respectively. When combining patients with scores of 1 and 2 into the middle risk group, and patients with scores of 0 and 3 into the low-risk and high-risk groups, respectively, different outcomes would be significantly distinguished by the risk groups. CONCLUSION Elevated ALP and GGT levels were risk predictors in HCC patients. Our prognostic model might vary the outcomes of patients from different risk groups.

Prognostic significance of pretreatment albumin/globulin ratio in patients with hepatocellular carcinoma

Background Pretreatment nutritional and immunological statuses play an indispensable role in predicting the outcome of patients with various types of malignancies. The purpose of this study is to evaluate the predictive value of albumin/globulin ratio (AGR) in overall survival (OS) and recurrence in patients with hepatocellular carcinoma (HCC) following radical hepatic carcinectomy. Patients and methods This retrospective study included a total of 172 patients with HCC with complete medical and follow-up information between 2002 and 2012. AGR was calculated according to the following formula: AGR = albumin/globulin. Receiver operating characteristic curve analysis was performed to determine the optimal cutoff value. The associations of AGR with clinicopathological characteristics and prognosis were assessed. Further multivariate analysis using Cox regression model and subgroup analysis was performed to evaluate the predictive value. Results Receiver operating characteristic curve determined 37.65, 31.99, and 1.48 as the optimal cutoff values of albumin, globulin, and AGR in terms of 5-year OS or death, respectively. On the basis of the cutoff value of AGR, all the patients were divided, respectively, into low-AGR (n=105) and high-AGR (n=67) groups. AGR was found to be significantly correlated with age, cancer embolus, international normalized ratio, and postoperative outcome (P<0.05). Hepatitis B virus infection (hazard ratio [HR]: 2.125; 95% confidence interval [CI]: 1.285–3.153), tumor node metastasis stage (HR: 1.656; 95% CI: 1.234–2.223), serum albumin (HR: 0.546; 95% CI: 0.347–0.857), and AGR (HR: 0.402; 95% CI: 0.233–0.691) were independent predictors of OS via univariate and multivariate survival analyses. However, alpha-fetoprotein (HR: 1.708; 95% CI: 1.027–2.838), tumor node metastasis stage (HR: 1.464; 95% CI: 1.078–1.989), and AGR (HR: 0.493; 95% CI: 0.293–0.828) functioned as independent risk variables for predicting recurrence. Moreover, AGR showed superior prognostic value for OS and recurrence in the subgroups with normal level of albumin or survival time beyond 6 months. Conclusion Pretreatment AGR might serve as an effective biomarker to evaluate the prognosis of patients with a diagnosis of HCC. Based on the results, AGR, characterized with easy accessibility, objectivity, and noninvasiveness, should be included in the routine assessment of HCC.

Association of cancer mortality with postdiagnosis overweight and obesity using body mass index.

Although overweight and obesity increase cancer risk, it is still controversial with respect to cancer mortality. In the current study, we enrolled 2670 patients of 14 tumor types from the Cancer Genome Atlas (TCGA) project, to identify the prognostic role of overweight and obesity in cancer patients. After dividing the patients into different groups by the body mass index (BMI), we found significant lower mortality in the obesity group. In addition, we also treat BMI value as a binary categorical variable or continuous variable, respectively. We found significant lower mortality in the higher BMI group. Furthermore, when focusing on each tumor type, cervical cancer and bladder cancer showed lower mortality in the patients with higher BMI values. Taken together, our results demonstrate that postdiagnosis obesity might indicate a better prognosis in cancer patients. However, these findings should be interpreted cautiously because of small sample size.

FoxM1 as a Novel Therapeutic Target for Cancer Drug Therapy

BACKGROUND Current cancer therapy mainly focuses on identifying novel targets crucial for tumorigenesis. The FoxM1 is of preference as an anticancer target, due to its significance in execution of mitosis, cell cycle progression, as well as other signal pathways leading to tumorigenesis. FoxM1 is partially regulated by oncoproteins or tumor suppressors, which are often mutated, lost, or overexpressed in human cancer. Since sustaining proliferating signaling is an important hallmark of cancer, FoxM1 is overexpressed in a series of human malignancies. Alarge- scale gene expression analysis also identified FoxM1 as a differentially-expressed gene in most solid tumors. Furthermore, overexpressed FoxM1 is correlated with the prognosis of cancer patients, as verified in a series of malignancies by Cox regression analysis. Thus, extensive studies have been conducted to explore the roles of FoxM1 in tumorigenesis, making it an attractive target for anticancer therapy. Several antitumor drugs have been reported to target or inhibit FoxM1 expression in different cancers, and down-regulation of FoxM1 also abrogates drug resistance in some cancer cell lines, highlighting a promising future for FoxM1 application in the clinic.

Significance of platelet count and platelet-based models for hepatocellular carcinoma recurrence

AIM To explore the effects of platelet count (PLT) and 11 platelet-based indices on postoperative recurrence of hepatocellular carcinoma (HCC). METHODS We retrospectively analyzed 172 HCC patients who were treated by partial hepatectomy. Preoperative data, including laboratory biochemical results, were used to calculate the 11 indices included in the analysis. We performed receiver operating characteristic curve analysis to determine the optimal cut-off values for predicting recurrence. Cumulative rates of HCC recurrence were calculated using Kaplan-Meier survival curves and differences were analyzed by log-rank tests. Multivariate analyses were performed to identify independent predictors of recurrence, early recurrence (within one year after surgery), and late recurrence in HCC. To obtain better prognostic models, PLT-based indices were analyzed separately after being expressed as binary and continuous variables. Two platelet-unrelated, validated HCC prognostic models were included in the analyses as reference indices. Additional analyses were performed after patients were stratified based on hepatitis B virus infection status, cirrhosis, and tumor size to investigate the significance of platelets in different subgroups. RESULTS In the study cohort, 44.2% (76/172) of patients experienced HCC recurrence, and 50.6% (87/172) died during a median follow-up time of 46 mo. PLT and five of the 11 platelet-related models were significant predisposing factors for recurrence (P < 0.05). Multivariate analysis indicated that, among the clinical parameters, presence of ascites, PLT ≥ 148 × 10(9)/L, alkaline phosphatase ≥ 116 U/L, and tumor size ≥ 5 cm were independently associated with a higher risk of HCC recurrence (P < 0.05). Independent and significant models included the aspartate aminotransferase/PLT index, fibrosis index based on the four factors, fibro-quotient, aspartate aminotransferase/PLT/γ-glutamyl transpeptidase/alpha-fetoprotein index, and the PLT/age/alkaline phosphatase/alpha-fetoprotein/aspartate aminotransferase index. There were different risk factors between early and late recurrences, and PLT and these indices were more inclined to influence late recurrence. PLT was only predictive of recurrence in non-cirrhotic HCC patients, and was not influenced by tumor size, which was a critical confounder in our study. CONCLUSION PLT and PLT-based noninvasive models are effective tools for predicting postoperative recurrence, especially late recurrence. Larger cohorts are needed to validate our findings.

THE PROTECTIVE ROLE OF CURCUMIN IN ZYMOSAN-INDUCED MULTIPLE ORGAN DYSFUNCTION SYNDROME IN MICE.

Aim: Multiple Organ Dysfunction Syndrome (MODS) is characterized as progressive and uncontrolled inflammatory response which involves activation of inflammatory cascades, cytokines release, and endothelial dysfunction, leading to deterioration of several organ functions. Curcumin is a natural polyphenol related to the yellow color of turmeric and has been reported to exert an anti-inflammatory, anti-oxidative, and anti-tumor effect. We conducted the study to investigate the effects of curcumin in non-septic MODS caused by zymosan in mice model. Method: The mice were randomly allocated into five groups (six mice per group): control group (treated with physiological saline, 0.1 mL daily for 3 days before and 1 h after physiological saline treatment), DMSO group (treated with DMSO, 0.1 mL daily for 3 days before and 1 h after physiological saline treatment), Curcumin group (200 mg/kg, suspended in DMSO, in a final volume of 0.1 mL, used for 3 days daily before and 1 h after physiological saline treatment), Zymosan+DMSO group (treated with DMSO, 0.1 mL daily for 3 days before and 1 h after zymosan treatment) and Zymosan+ Curcumin group (treated with curcumin, suspended in DMSO at a dose of 0.1 mL daily for 3 days before and 1 h after zymosan treatment). Mice in groups were sacrificed, and then the blood and tissues were collected to evaluate the severity of acute peritonitis, tissue histopathological changes, NO formation, oxidative stress, PMN infiltration, cytokines production, organ function, and NF-&kgr;B activation 18 h after when zymosan or physiological saline was injected. In another set of experiments, the mice were also grouped (20 mice per group) for monitoring the loss of body weight and mortality for 7 days after zymosan or physiological saline administration. Results: Curcumin induces a significant reduction of the volume exudate and the neutrophil infiltration. It also could exhibit an outstanding protective effect against histopathological injury by decreasing the NO formation, oxidative stress, cytokines production, and infiltration of inflammatory cells. The organ function is also improved by administration of curcumin. Moreover, the activation of NF-&kgr;B is attenuated by curcumin in the MODS mice model, suggesting that curcumin attenuated the zymosan-induced MODS via inhibiting the expression of NF-&kgr;B possibly. In addition, curcumin-treated mice were shown to alleviate the severity of MODS characterized by a minor systemic toxicity, less body weight loss, and lower mortality caused by zymosan administration. Conclusion: Curcumin attenuates zymosan-induced MODS.

Simple models based on gamma-glutamyl transpeptidase and platelets for predicting survival in hepatitis B-associated hepatocellular carcinoma

Background Several hepatic cirrhosis-derived noninvasive models have been developed to predict the incidence and outcomes of hepatocellular carcinoma (HCC). We aimed to investigate the prognostic significance of the two novel established cirrhosis-associated models based on gamma-glutamyl transpeptidase (GGT) and platelets in hepatitis B-associated HCC. Methods We retrospectively evaluated 182 HCC patients with positive hepatitis B surface antigen who received radical therapy at a single institution between 2002 and 2012. Laboratory data prior to operation were collected to calculate the GGT to platelets ratio (GPR) and the S-index. Predictive factors associated with overall survival and recurrence-free survival were assessed using log-rank test and multivariate Cox analysis. Additional analyses were performed after patients were stratified based on cirrhosis status, tumor size, therapy methods, and so forth, to investigate the prognostic significance in different subgroups. Results During a median follow-up time of 45.0 months, a total of 88 (48.4%) patients died and 79 (43.4%) patients recurred. The cut-off points for GPR and S-index in predicting death were determined to be 0.76 and 0.56, respectively. Compared with patients with a lower GPR, those with GPR ≥0.76 had a higher probability of cirrhosis and a larger tumor (both P<0.05). GPR and S-index were both found to be significantly associated with survival by univariate log-rank test. Multivariate analysis identified tumor size ≥5 and high level of GPR, but not high Barcelona Clinic Liver Cancer stage or S-index, as independent factors for predicting poor overall survival and recurrence-free survival. Conclusion The GPR is an effective preoperative predictor for outcomes in hepatitis B-associated HCC.

Transcriptional modules related to hepatocellular carcinoma survival: coexpression network analysis

We performed weighted gene coexpression network analysis (WGCNA) to gain insights into the molecular aspects of hepatocellular carcinoma (HCC). Raw microarray datasets (including 488 samples) were downloaded from the Gene Expression Omnibus (GEO) website. Data were normalized using the RMA algorithm. We utilized the WGCNA to identify the coexpressed genes (modules) after non-specific filtering. Correlation and survival analyses were conducted using the modules, and gene ontology (GO) enrichment was applied to explore the possible mechanisms. Eight distinct modules were identified by the WGCNA. Pink and red modules were associated with liver function, whereas turquoise and black modules were inversely correlated with tumor staging. Poor outcomes were found in the low expression group in the turquoise module and in the high expression group in the red module. In addition, GO enrichment analysis suggested that inflammation, immune, virus-related, and interferon-mediated pathways were enriched in the turquoise module. Several potential biomarkers, such as cyclin-dependent kinase 1 (CDK1), topoisomerase 2α (TOP2A), and serpin peptidase inhibitor clade C (antithrombin) member 1 (SERPINC1), were also identified. In conclusion, gene signatures identified from the genome-based assays could contribute to HCC stratification. WGCNA was able to identify significant groups of genes associated with cancer prognosis.